Alpha particles (i.e., helium nuclei) are significantly more effective in killing tumor cells than either conventional external beam therapy or beta particle emitters such as 90Y and 131I, which are employed in the commercially available radioimmunotherapy agents Zevalin® and Bexxar®, respectively. This is due to the high linear energy transfer (˜100 keV/μm) and short path length (<100 μm) of α-particles. They can thus focus large amounts of energy over only a few cell diameters. These properties allow for the targeting of specific tumor cells with minimal damage to surrounding healthy tissues.
Of the potential α-particle emitters, 211At is especially desirable for targeted radiotherapy. 211At, produced by the cyclotron bombardment of stable 209Bi with an α-particle beam, has a half-life of 7.2 hours. Theoretically, this is sufficient to allow for the preparation of radiopharmaceuticals and even for their delivery to remote sites with a therapeutically effective level of radioactivity. These considerations have led to the investigation of attaching 211At to various molecules. Zalutsky, M. et al., CURR PHARM DES. 6:1433-1455 (2000); Wilbur, D., et al., NUCL MED BIOL. 20:917-927 (1993); Wilbur, D. et al., BIOCONJUG CHEM. 15:203-223 (2004); and Link, E., HYBRIDOMA 18:77-82 (1999). The toxicity of 211At-labeled pharmaceuticals to cancer cells has been studied in cell cultures. Larsen, R. et al., INT J RADIAT BIOL. 72:79-90 (1997); Larsen, R. et al., RADIAT RES. 149:155-162 (1998); Walicka, M. et al., RADIAT RES. 150:263-268 (1998); and Zalutsky, M. et al., Proc Am Assoc Cancer Res. 43:481 (2002). Treatment of tumors in animal models with these agents has also been performed. Larsen, R. et al., BR J CANCER 77:1115-1122 (1998); Garg, P. et al, CANCER RES. 50:3514-3520 (1990); Andersson, H. et al., ANTICANCER RES. 21:409-412 (2001). A clinical trial with 211At-labeled monoclonal antibodies has been undertaken at Duke University Medical Center. Zalutsky, M. et al., NEURO-ONCOLOGY 4(suppl):S103 (2002) and Zalutsky, M. BR J CANCER 90:1469-1473 (2004).
As a practical matter, however, the potential benefits of 211At therapy have not been realized. The alpha radiation that 211At produces converts astatine into a chemical form that is not easily incorporated into pharmaceuticals or precursor compounds. As a result, the yield of the 211At-labeled pharmaceutical or 211At-labeled precursor compound decreases dramatically with increasing radiation dose.
The general importance of radiolytic effects in the preparation of radiolabeled pharmaceuticals has been reported. Bayly, R. et al., J LABELLED COMPD. 2:1-34 (1966). Also, the stability of positron-emitting radiopharmaceuticals has been studied, including the effects of radical scavengers on stability. Fukumura, T., et al., APPL RADIAT ISOT. 61:1279-1287 (2004); Bogni, A. et al, J RADIOANAL NUCL CHEM. 256:199-203 (2003); Fukumura, T. et al, NUCL MED BIOL. 30:389-395 (2004); and Fukumura, T. et al., RADIOCHIM ACTA 92:119-123 (2004). More recently, the effects of solvent type, radiation dose, and other variables on the yield of 211At-labeled precursor compounds of significant interest for cancer therapy have been evaluated. Pozzi, O. et al., J NUCL MED. 46:1393-1400 (2005) and Pozzi, O. et al., J NUCL MED. 46:700-706 (2005).
Substantial difficulties remain in the production of pharmaceuticals labeled with 211At or other α-particle emitters at radioactivity levels sufficient for therapeutic applications. These high radioactivity levels, over the course of reagent solution preparation, storage, and use in preparing radiolabeled pharmaceuticals, invariably result in a cumulative radiation dose from α-particles that is detrimental to the labeling chemistry. Undesired radiolytic effects include loss of precursor (e.g., organic tin compounds) and reactive 211At through their interaction with free radicals, generated by the radiolysis of the reaction solution. For example, in the case of alpha radiation absorbed by methanol, especially under acidic conditions, the formation of reducing species (e.g., hydrogen and formaldehyde) is believed to contribute to the losses in the yield of 211At-labeled compounds.
The detrimental radiolytic effects described above have greatly complicated the synthesis of α-particle emitter labeled pharmaceuticals having therapeutically effective levels of radioactivity. This is especially true in cases where it is desired to prepare these pharmaceuticals in a location that is remote from the site of production of the α-particle emitter. The time required for shipping necessarily increases the radiation dose received by the α-particle emitter-containing reagent solution, thereby promoting the radiolytic effects that have shown to decrease yields of the α-particle emitter labeled pharmaceutical end product.